Lipoprotein retention by extracellular vascular matrix molecules plays an important role in several stages of atherogenesis. This project evaluates how lipoprotein-matrix interactions can be altered in diabetes as a possible explanation for the markedly increased cardiovascular risk associated with this disorder. Several factors associated with the diabetic state will be tested for their ability to influence the interaction of atherogenic lipoproteins with the vascular extracellular matrix. These include oxidative stress, glucose and FFA, and reactive carbonyls. Proteoglycans are the class of molecules that are most important in the retention of atherogenic lipoproteins in the artery wall. In Specific Aim 1, we will determine the role of oxidative stress, which is increased in the artery wall in diabetes, on the regulation of proteoglycan synthesis by vascular smooth muscle cells and macrophages, ultimately leading to increased retention of atherogenic lipoproteins. In Specific Aim 2, we will determine the roles and mechanisms by which glucose and FFA, both of which also are hallmarks of diabetes, modulates vascular proteoglycans so as to influence the retention of atherogenic lipoproteins. This includes the role of reactive carbonyls, which are formed during glycation reactions. These carbonyls will be tested for their ability to modulate proteoglycan synthesis. The impact of carbonyl modification of matrix molecules on lipoprotein retention also will be tested. Aims 1 and 2 will use both in vitro and in vivo models. Specific Aim 3 will focus on the regulation of the synthesis of hyaluronan in diabetes in vitro and in vivo. Hyaluronan is a matrix molecule that appears to play a prominent role in atherosclerotic lesions in diabetes. In this Aim we will evaluate the ability of several factors associated with the diabetic state, such as oxidative stress, glucose, FFA and insulin, to alter hyaluronan secretion by both vascular smooth muscle cells and macrophages, and we will study potential mechanisms by which hyaluronan might potentiate atherosclerosis. Project 17 will use several approaches and models in common with Projects 18 and 20, and will provide new insights into the pathogenesis of macrovascular disease in diabetes.